Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study

Sepsis is the leading cause of death in intensive care units and a major public health concern in the world. Heparin, a widely used anticoagulant medicine to prevent or treat thrombotic disorders, has been demonstrated to prevent organ damage and lethality in experimental sepsis models. However, the efficacy of heparin in the treatment of clinical sepsis is not consistent. Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Recently, we have revealed that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1- LPS interaction, which is independent of its anticoagulant properties. In our study, it is found that heparin treatment could prevent lethal responses in endotoxemia or Gram-negative sepsis, while caspase-11 deficiency or heparin treatment failed to confer protection against sepsis caused by Staphylococcus aureus, a type of Gram-positive bacterium. It is probably that other pathogens such as Gram-positive bacteria might cause death through mechanisms distinct from that of Gram-negative bacteria. Peptidoglycan, a cell-wall component of Gram-positive bacteria, can cause DIC and impair survival in primates by activating both extrinsic and intrinsic coagulation pathways, which might not be targeted by heparin. We speculate that the discrepancy between the previous clinical trials of heparin might be due to the difference in infected pathogens. Thus, stratification of patients based on the type of invading pathogens might improve the therapeutic efficiency of heparin in sepsis, and this merits future investigations.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Gram-Negative Bacterial Infections; Heparin
• Intervention / Treatment: Drug: Unfractionated Heparin

Detailed Description

In clinical patients, the major pathogens of sepsis caused by abdominal infection are mostly Gram-negative bacterium. Therefore, aim of this study is to determine effects of low dose unfractionated heparin for treatment of sepsis caused by abdominal infection.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Recruiting
      • The Third Xiangya Hospital, Central South University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients will be eligible for inclusion if all of the inclusion criteria are met:

1.Sepsis-3 criteria from Society of Critical Care Medicine (SCCM) /European Society of Intensive Care Medicine (ESICM), and the infection site is from abdomen 2.18≤ age ≤75years 3.obtain informed consent

Exclusion Criteria:

1. The primary site of infection is from other parts (such as lungs, intracranial, etc.) except abdomen
2. Diagnosis of sepsis for more than 48 hour
3. Pregnant and lactating women
4. Severe primary disease including unrespectable tumours, blood diseases and Human Immunodeficiency Virus (HIV);
5. Have a known or suspected adverse reaction to UFH including HIT
6. Have bleeding or high risk for bleeding
7. Have an indication for therapeutic anticoagulation or have taken anticoagulants within 7 days
8. Use of an immunosuppressant or having an organ transplant within the previous 6 months
9. Participating in other clinical trials in the previous 30 days
10. Have received cardiopulmonary resuscitation within 7 days
11. Have terminal illness with a life expectancy of less than 28 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Unfractionated Heparin; A bottle solution of Heparin Sodium (2ml:12500IU) is added to 48 ml saline and administered intravenously continuously for 24 hours (10 unit/kgBW/hour), which last 5 days or until the death or discharge.	Drug: Unfractionated Heparin; 10 unit/kgBW/hour continuous infusion for 5 days; Other Names: Heparin sodium
Placebo Comparator: Normal saline; The same amount of 0.9% saline as the heparin group (50ml) will be administered in the placebo group.	Drug: Unfractionated Heparin; 10 unit/kgBW/hour continuous infusion for 5 days; Other Names: Heparin sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-Cause Mortality	Death from all causes at 28-days	28 Days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death in ICU	Death from all causes at ICU discharge	28 Days after randomization
SOFA score	Total Sequential Organ Failure Assessment (SOFA) score(0-24) , higher values represent a worse outcome	Day 0,3,6 after randomization
APACHEⅡ	Acute Physiology and Chronic Health Evaluation (include Acute physiology score, APS and age and Chronic physiology score, totally 0-71 Points)	Day 0,3,6 after randomization
SIC score	Sepsis-induced coagulopathy score (totally 0-6 Points)	Day 0,3,6 after randomization
DIC score	Disseminated intravascular coagulation score (totally 0-8 Points)	Day 0,3,6 after randomization
Duration of mechanical ventilation and continuous renal replacement therapy	Duration of mechanical ventilation and continuous renal replacement therapy in ICU	28 days after randomization
ICU stay	Duration of stay in ICU	28 days after randomization
Inflammation	Concentration of inflammation markers such as c-reactive protein, procalcitonin, IL-1β and IL-1α at 0, 3,6 days after randomization	0,3,6 days after randomization
Coagulation	Concentration of coagulation related indexes such as fibrinogen degradation products, d-dimer, thrombin-antithrombin complex, plasminogen activator inhibitor-1, plasmin antiplasmin complex, and thrombomodulin at 0,3,6 days after randomization	0,3,6 days after randomization
The incidence of major bleeding	"Major bleeding" is defined as intracranial bleeding, life-threatening bleeding, or need red blood cell suspension more than 3 units every 24 hours, and last for 2 days	28 days after randomization

Collaborators and Investigators

• Sponsor: The Third Xiangya Hospital of Central South University
• Collaborators: Xiangya Hospital of Central South University; Wuhan Union Hospital, China; Central South University; The Second Hospital of South China University; The Affiliated Yantai Yuhuangding Hospital of Qingdao University

Publications and helpful links

General Publications

• Tang Y, Wang X, Li Z, He Z, Yang X, Cheng X, Peng Y, Xue Q, Bai Y, Zhang R, Zhao K, Liang F, Xiao X, Andersson U, Wang H, Billiar TR, Lu B. Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties. Immunity. 2021 Mar 9;54(3):454-467.e6. doi: 10.1016/j.immuni.2021.01.007. Epub 2021 Feb 8.
• Deng M, Tang Y, Li W, Wang X, Zhang R, Zhang X, Zhao X, Liu J, Tang C, Liu Z, Huang Y, Peng H, Xiao L, Tang D, Scott MJ, Wang Q, Liu J, Xiao X, Watkins S, Li J, Yang H, Wang H, Chen F, Tracey KJ, Billiar TR, Lu B. The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis. Immunity. 2018 Oct 16;49(4):740-753.e7. doi: 10.1016/j.immuni.2018.08.016. Epub 2018 Oct 9.
• Yang X, Cheng X, Tang Y, Qiu X, Wang Y, Kang H, Wu J, Wang Z, Liu Y, Chen F, Xiao X, Mackman N, Billiar TR, Han J, Lu B. Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure. Immunity. 2019 Dec 17;51(6):983-996.e6. doi: 10.1016/j.immuni.2019.11.005. Epub 2019 Dec 10.
• Yang X, Cheng X, Tang Y, Qiu X, Wang Z, Fu G, Wu J, Kang H, Wang J, Wang H, Chen F, Xiao X, Billiar TR, Lu B. The role of type 1 interferons in coagulation induced by gram-negative bacteria. Blood. 2020 Apr 2;135(14):1087-1100. doi: 10.1182/blood.2019002282.
• Lu Y, Meng R, Wang X, Xu Y, Tang Y, Wu J, Xue Q, Yu S, Duan M, Shan D, Wang Q, Wang H, Billiar TR, Xiao X, Chen F, Lu B. Caspase-11 signaling enhances graft-versus-host disease. Nat Commun. 2019 Sep 6;10(1):4044. doi: 10.1038/s41467-019-11895-2. Erratum In: Nat Commun. 2020 Mar 9;11(1):1349.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2021
• Primary Completion (Anticipated): December 30, 2023
• Study Completion (Anticipated): July 30, 2024

Study Registration Dates

• First Submitted: April 22, 2021
• First Submitted That Met QC Criteria: April 25, 2021
• First Posted (Actual): April 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 21, 2023
• Last Update Submitted That Met QC Criteria: March 20, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections and Mycoses; Sepsis; Toxemia; Infections; Communicable Diseases; Intraabdominal Infections; Bacterial Infections; Gram-Negative Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: XY3-UFH2021

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No